tbuckley/cabot-search huggingface dataset:
Evaluation and Management of Pulmonary Hypertension in Noncardiac Surgery: A Scientific Statement From the American Heart Association
Authors: Sudarshan Rajagopal, Kurt Ruetzler, Kamrouz Ghadimi, Evelyn M. Horn, Marta Kelava, Kristina T. Kudelko, Ingrid Moreno-Duarte, Ioana Preston, Leonie L. Rose Bovino, Nathaniel R. Smilowitz, Anjali Vaidya
Journal: Circulation (2023)

Pulmonary hypertension, defined as an elevation in blood pressure in the pulmonary arteries, is associated with an increased risk of death. The prevalence of pulmonary hypertension is increasing, with an aging population, a rising prevalence of heart and lung disease, and improved pulmonary hypertension survival with targeted therapies. Patients with pulmonary hypertension frequently require noncardiac surgery, although pulmonary hypertension is associated with excess perioperative morbidity and death. This scientific statement provides guidance on the evaluation and management of pulmonary hypertension in patients undergoing noncardiac surgery. We advocate for a multistep process focused on (1) classification of pulmonary hypertension group to define the underlying pathology; (2) preoperative risk assessment that will guide surgical decision-making; (3) pulmonary hypertension optimization before surgery to reduce perioperative risk; (4) intraoperative management of pulmonary hypertension to avoid right ventricular dysfunction and to maintain cardiac output; and (5) postoperative management of pulmonary hypertension to ensure recovery from surgery. Last, this scientific statement highlights the paucity of evidence to support perioperative pulmonary hypertension management and identifies areas of uncertainty and opportunities for future investigation.
Splanchnic nerve block with botulinum toxin for therapy of chronic heart failure – mechanism of action (<scp>SPONGE‐HF</scp>)
Authors: Marat Fudim, Kishan Parikh, Arun Ganesh, Jeroen Molinger, Neil Ray, Aubrie Coburn, Brian J. Coyne, Ashley G. Swavely, Jennifer Andrews, James Matthew Gray, Vishal N. Rao, G. Michael Felker, Salvador Borges‐Neto, Adrian F. Hernandez, Manesh R. Patel
Journal: European Journal of Heart Failure (2023)
Intrinsic RIG-I restrains STAT5 activation to modulate anti-tumor activity of CD8+ T cells
Authors: Xinyi Jiang, Jian Lin, Chengfang Shangguan, Xiaoyao Wang, Bin Xiang, Juan Chen, Hezhou Guo, Wu Zhang, Jun Zhang, Yan Shi, Jiang Zhu, Hui Yang
Journal: Journal of Clinical Investigation (2023)

Antitumor activity of CD8+ T cells is potentially restrained by a variety of negative regulatory pathways that are triggered in the tumor microenvironment, yet, the exact mechanisms remain incompletely defined. Here, we report that intrinsic RIG-I in CD8+ T cells represents such a factor, as evidenced by observations that the tumor-restricting effect of endogenous or adoptively transferred CD8+ T cells was enhanced by intrinsic Rig-I deficiency or inhibition, with the increased accumulation, survival, and cytotoxicity of tumor-infiltrating CD8+ T cells. Mechanistically, T cell activation-induced RIG-I upregulation restrained STAT5 activation via competitive sequestering of HSP90. In accordance with this, the frequency of RIG-I+ tumor-infiltrating CD8+ T cells in human colon cancer positively correlated with attenuated survival and effector signatures of CD8+ T cells as well as poor prognosis. Collectively, these results implicate RIG-I as a potentially druggable factor for improving CD8+ T cell-based tumor immunotherapy.
RIP140 deficiency enhances cardiac fuel metabolism and protects mice from heart failure
Authors: Tsunehisa Yamamoto, Santosh K. Maurya, Elizabeth Pruzinsky, Kirill Batmanov, Yang Xiao, Sarah M. Sulon, Tomoya Sakamoto, Yang Wang, Ling Lai, Kendra S. McDaid, Swapnil V. Shewale, Teresa C. Leone, Timothy R. Koves, Deborah M. Muoio, Pieterjan Dierickx, Mitchell A. Lazar, E. Douglas Lewandowski, Daniel P. Kelly
Journal: Journal of Clinical Investigation (2023)

During the development of heart failure (HF), the capacity for cardiomyocyte (CM) fatty acid oxidation (FAO) and ATP production is progressively diminished, contributing to pathologic cardiac hypertrophy and contractile dysfunction. Receptor-interacting protein 140 (RIP140, encoded by Nrip1) has been shown to function as a transcriptional corepressor of oxidative metabolism. We found that mice with striated muscle deficiency of RIP140 (strNrip1-/-) exhibited increased expression of a broad array of genes involved in mitochondrial energy metabolism and contractile function in heart and skeletal muscle. strNrip1-/- mice were resistant to the development of pressure overload-induced cardiac hypertrophy, and CM-specific RIP140-deficient (csNrip1-/-) mice were protected against the development of HF caused by pressure overload combined with myocardial infarction. Genomic enhancers activated by RIP140 deficiency in CMs were enriched in binding motifs for transcriptional regulators of mitochondrial function (estrogen-related receptor) and cardiac contractile proteins (myocyte enhancer factor 2). Consistent with a role in the control of cardiac fatty acid oxidation, loss of RIP140 in heart resulted in augmented triacylglyceride turnover and fatty acid utilization. We conclude that RIP140 functions as a suppressor of a transcriptional regulatory network that controls cardiac fuel metabolism and contractile function, representing a potential therapeutic target for the treatment of HF.
Keratinocytes sense and eliminate CRISPR DNA through STING/IFN-κ activation and APOBEC3G induction
Authors: Mrinal K. Sarkar, Ranjitha Uppala, Chang Zeng, Allison C. Billi, Lam C. Tsoi, Austin Kidder, Xianying Xing, Bethany E. Perez White, Shuai Shao, Olesya Plazyo, Sirisha Sirobhushanam, Enze Xing, Yanyun Jiang, Katherine A. Gallagher, John J. Voorhees, J. Michelle Kahlenberg, Johann E. Gudjonsson
Journal: Journal of Clinical Investigation (2023)

CRISPR/Cas9 has been proposed as a treatment for genetically inherited skin disorders. Here we report that CRISPR transfection activates STING-dependent antiviral responses in keratinocytes, resulting in heightened endogenous interferon (IFN) responses through induction of IFN-κ, leading to decreased plasmid stability secondary to induction of the cytidine deaminase gene APOBEC3G. Notably, CRISPR-generated KO keratinocytes had permanent suppression of IFN-κ and IFN-stimulated gene (ISG) expression, secondary to hypermethylation of the IFNK promoter region by the DNA methyltransferase DNMT3B. JAK inhibition via baricitinib prior to CRISPR transfection increased transfection efficiency, prevented IFNK promoter hypermethylation, and restored normal IFN-κ activity and ISG responses. This work shows that CRISPR-mediated gene correction alters antiviral responses in keratinocytes, has implications for future gene therapies for inherited skin diseases using CRISPR technology, and suggests pharmacologic JAK inhibition as a tool for facilitating and attenuating inadvertent selection effects in CRISPR/Cas9 therapeutic approaches.
Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas
Authors: Marina Salmón, Ruth Álvarez-Díaz, Coral Fustero-Torre, Oksana Brehey, Carmen G. Lechuga, Manuel Sanclemente, Fernando Fernández-García, Alejandra López-García, María Carmen Martín-Guijarro, Sandra Rodríguez-Perales, Emily Bousquet-Mur, Lucía Morales-Cacho, Francisca Mulero, Fátima Al-Shahrour, Lola Martínez, Orlando Domínguez, Eduardo Caleiras, Sagrario Ortega, Carmen Guerra, Monica Musteanu, Matthias Drosten, Mariano Barbacid
Journal: Journal of Clinical Investigation (2023)

KRASG12C inhibitors have revolutionized the clinical management of patients with KRASG12C-mutant lung adenocarcinoma. However, patient exposure to these inhibitors leads to the rapid onset of resistance. In this study, we have used genetically engineered mice to compare the therapeutic efficacy and the emergence of tumor resistance between genetic ablation of mutant Kras expression and pharmacological inhibition of oncogenic KRAS activity. Whereas Kras ablation induces massive tumor regression and prevents the appearance of resistant cells in vivo, treatment of KrasG12C/Trp53-driven lung adenocarcinomas with sotorasib, a selective KRASG12C inhibitor, caused a limited antitumor response similar to that observed in the clinic, including the rapid onset of resistance. Unlike in human tumors, we did not observe mutations in components of the RAS-signaling pathways. Instead, sotorasib-resistant tumors displayed amplification of the mutant Kras allele and activation of xenobiotic metabolism pathways, suggesting that reduction of the on-target activity of KRASG12C inhibitors is the main mechanism responsible for the onset of resistance. In sum, our results suggest that resistance to KRAS inhibitors could be prevented by achieving a more robust inhibition of KRAS signaling mimicking the results obtained upon Kras ablation.
Persistent fasting lipogenesis links impaired ketogenesis with citrate synthesis in humans with non-alcoholic fatty liver
Authors: Xiaorong Fu, Justin A. Fletcher, Stanisław Deja, Melissa Inigo-Vollmer, Shawn C. Burgess, Jeffrey D. Browning
Journal: Journal of Clinical Investigation (2023)

BACKGROUNDHepatic de novo lipogenesis (DNL) and β-oxidation are tightly coordinated, and their dysregulation is thought to contribute to the pathogenesis of nonalcoholic fatty liver (NAFL). Fasting normally relaxes DNL-mediated inhibition of hepatic β-oxidation, dramatically increasing ketogenesis and decreasing reliance on the TCA cycle. Thus, we tested whether aberrant oxidative metabolism in fasting NAFL subjects is related to the inability to halt fasting DNL.METHODSForty consecutive nondiabetic individuals with and without a history of NAFL were recruited for this observational study. After phenotyping, subjects fasted for 24 hours, and hepatic metabolism was interrogated using a combination of 2H2O and 13C tracers, magnetic resonance spectroscopy, and high-resolution mass spectrometry.RESULTSWithin a subset of subjects, DNL was detectable after a 24-hour fast and was more prominent in those with NAFL, though it was poorly correlated with steatosis. However, fasting DNL negatively correlated with hepatic β-oxidation and ketogenesis and positively correlated with citrate synthesis. Subjects with NAFL but undetectable fasting DNL (25th percentile) were comparatively normal. However, those with the highest fasting DNL (75th percentile) were intransigent to the effects of fasting on the concentration of insulin, non-esterified fatty acid, and ketones. Additionally, they sustained glycogenolysis and were spared the loss of oxaloacetate to gluconeogenesis in favor of citrate synthesis, which correlated with DNL and diminished ketogenesis.CONCLUSIONMetabolic flux analysis in fasted subjects indicates that shared metabolic mechanisms link the dysregulations of hepatic DNL, ketogenesis, and the TCA cycle in NAFL.TRIAL REGISTRATIONData were obtained during the enrollment/non-intervention phase of Effect of Vitamin E on Non-Alcoholic Fatty Liver Disease, ClinicalTrials.gov NCT02690792.FUNDINGThis work was supported by the University of Texas Southwestern NORC Quantitative Metabolism Core (NIH P30DK127984), the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (R01DK078184, R01DK128168, R01DK087977, R01DK132254, and K01DK133630), the NIH/National Institute on Alcohol Abuse and Alcoholism (K01AA030327), and the Robert A. Welch Foundation (I-1804).
NSAID-exacerbated respiratory disease, dupilumab and aspirin tolerance
Authors: Donald W. Cockcroft
Journal: European Respiratory Journal (2023)

<b>Schneider <i>et al</i>. add to the growing evidence that dupilumab is very effective in N-ERD inducing increased tolerance to ASA in 57% of patients (complete in 23%), accompanied by improvements in both upper and lower airway clinical features of disease</b>https://bit.ly/3jqs1DC
Angelica herbal supplement AGN-CognI.Q acute dose safety and pharmacokinetics (PK) dose-response in patients with prostate cancer (PK Dose Trial).
Authors: Monika Joshi, Jay D. Raman, Xin Liu, Doris Shank, Todd D. Schell, Jiangang Jason Liao, Junxuan Lu
Journal: Journal of Clinical Oncology (2023)

TPS404 Background: There are currently no FDA approved modalities for intercepting biochemically recurrent prostate cancer (PCa) after standard of care surgery and radiation therapies to delay or prevent the need of androgen deprivation therapy (ADT) for localized disease. Preclinical modeling has suggested herbal alcoholic extracts of Angelica gigas Nakai (AGN) root, their signature pyranocoumarins and metabolite decursinol, as potential novel modalities to address this unmet clinical need. We hypothesize that CognI.Q at the higher doses has an acceptable safety profile in prostate cancer patients and pharmacokinetics (PK) exposure metrics will be increased proportional to dose increment. Methods: This is a single institution, phase 1 PK study, N=12. Primary objective- PK, pharmacodynamic (PD) biomarkers with a single ascending dose (SAD)-PK response design. After a subject is enrolled, a 14-day gap must occur before the next subject can be enrolled. If one subject develops a dose limiting toxicity (DLT) at any dose level, that subject will stop participation; If a 2 nd subject develops DLT at the same dose level, the trial will be stopped, and the dose level below will be the maximum tolerated dose (MTD). Any subject at a higher dose level at the time of occurrence of 2 nd DLT will also stop participation. All subjects will initially start at the 800 mg x 1dose, with further single dose escalation to 1200mg, 1600mg, 2000mg doses of AGN-CognI.Q; each dose will be 1-2 weeks apart. Inclusion criteria: Treated PCa, not on ADT; no active cancer. Subjects will be assessed for safety- clinical, labs (CBC, CMP, baseline and after 24hrs) and EKGs. PK blood will be taken at hourly intervals from 2-7hrs and 24hrs. Plasma pyranocoumarin content will be measured by LC-MS. Immunophenotyping of NK and T cell subtypes will be assessed at baseline and 24 h. Primary Endpoint: MTD. Secondary Endpoint: PK metrics; genotype CYP 2C19 and 3A4 metabolizer status and explore relationship to PK metrics and safety metrics; NK and inflammatory and immune cytokines as PD biomarkers. Trial is now open to accrual (Clinical trial registration NCT05375539). We anticipate that the acute dose safety and PK/PD information will inform the optimal design and execution of the longer-term safety and efficacy (phase I/II) trials. Research Support: MPI 1R01CA260901-01A. Clinical trial information: Clinical trial registration NCT05375539 .
Withdrawing Life Support
Authors: Thomas A. Raffin
Journal: JAMA (1995)

Withholding and withdrawal of life support in intensive care units (ICUs) has become the norm rather than the exception in the United States since the mid 1980s.<sup>1,2</sup>We are all familiar with the tremendous impact of the Karen Ann Quinlan case in 1976, the report of the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research in 1983, and the subsequent flurry of position statements from a multitude of individuals and professional organizations (for example, the American Thoracic Society) underscoring the fundamental right of patients or legal surrogates to refuse unwanted medical therapies.<sup>3-5</sup>Several clinical studies during the past few years have revealed that 40% to 65% of ICU deaths have been preceded by decisions to withhold or withdraw life support. In some cases, the percentage is even higher.<sup>6,7</sup>Health care professionals are responsible for informing patients, families, and surrogates about
DNR in the OR
Authors: Robert M. Walker
Journal: JAMA (1991)

Should do-not-resuscitate (DNR) orders be routinely rescinded when terminally ill patients undergo palliative surgery? If so, patients will be forced to balance the benefits of palliative surgery against the risks of unwanted resuscitation. If physicians are required to honor intraoperative DNR orders, they may feel unacceptably restrained from correcting adverse effects for which they feel responsible. This dilemma has been overlooked by DNR policies. This article argues for the permissibility of honoring intraoperative DNR orders. The patient's right to refuse treatment outweighs physicians' concerns about professional scrutiny over intraoperative deaths. Physicians' moral concerns about hastening patient death are important but may be assuaged by (1) emphasizing patients' acceptance of operative mortality risk; (2) viewing matters as analogous to surgery on Jehovah's Witnesses who refuse lifesaving transfusion; (3) viewing the patient's intraoperative death as a double effect, that is, an unintended negative effect that is linked to the performance of a good act (palliation); and (4) distinguishing this from assisted suicide. (JAMA. 1991;266:2407-2412)
Childhood Trachoma in a Nonendemic Area
Authors: Carl H. Mordhorst
Journal: JAMA (1978)

During ten years of study of<i>Chlamydia trachomatis</i>eye infections, trachoma was diagnosed in 14 Danish patients with onset during childhood. Clinical findings in the eye were characteristic of classical trachoma. The infecting<i>C trachomatis</i>immunotype was identified in all but one case. At the time of diagnosis, seven patients were still children (6 to 10 years of age), three were teenagers, and four were adults. In five young girls the disease was extremely severe. Delay in proper diagnosis and adequate therapy contributed to the prolongation and severity of the disease. Failure to diagnose is attributed to widespread opinion and teaching of physicians in Western countries that trachoma eye disease has disappeared. Studies of family members and other contacts of the patients contributed to an understanding of the pathogenesis of this disease. The source of initial eye infection with<i>C trachomatis</i>organisms in these cases was thought to be the birth canal. It was further postulated that reinfection of the eyes of these children occurred either from a reservoir in their own or their mother's genital tract. (<i>JAMA</i>239:1765-1771, 1978)
Septic Reactions to Platelet Transfusions
Authors: John F. Morrow
Journal: JAMA (1991)

<h3>Objective.</h3> —To determine the medical and laboratory characteristics of bacteremia secondary to transfusion of microbiologically contaminated platelet concentrates. <h3>Design.</h3> —Febrile transfusion reactions were prospectively monitored over 42 months. Units involved in reactions were evaluated with Gram's stain and culture tests. <h3>Setting.</h3> —Comprehensive cancer center. <h3>Patients.</h3> —Patients receiving platelet transfusions for thrombocytopenia secondary to bone marrow failure. <h3>Result.</h3> —Seven cases of transfusion-associated sepsis were observed. Multidonor platelet products stored for 5 days resulted in an incidence of sepsis five times higher than those stored for 4 days or less (<i>P</i>&lt;.01). Investigation indicates that contamination most likely occurred at the time of blood collection. Clinically, septic reactions were associated with greater temperature elevations (average increase, 2.0°C) than febrile reactions to sterile products. <h3>Conclusions.</h3> —Contamination of platelet concentrates remains a significant clinical problem. Septic episodes may be reduced by transfusion of platelets with shorter storage intervals. (<i>JAMA</i>. 1991;266:555-558)
Further follow up of mortality and incidence of cancer in men from the United Kingdom who participated in the United Kingdom's atmospheric nuclear weapon tests and experimental programmes.
Authors: S C Darby, G M Kendall, T P Fell, R Doll, A A Goodill, A J Conquest, D A Jackson, R G Haylock
Journal: BMJ (1993)

OBJECTIVES--To study the long term effects of participation in the United Kingdom9s atmospheric nuclear weapon tests and experimental programmes and to test hypotheses generated by an earlier report, including the possibility that participation in tests caused small hazards of leukaemia and multiple myeloma. DESIGN--Follow up study of mortality and cancer incidence. SUBJECTS--21,358 servicemen and civilians from the United Kingdom who participated in the tests and a control group of 22,333 non-participants. MAIN OUTCOME MEASURES--Numbers of deaths; standardised mortality ratios; relative risks of mortality from all causes and 27 types of cancer. RESULTS--During seven further years of follow up the numbers of deaths observed in participants were fewer than expected from national rates for all causes, all neoplasms, leukaemia, and multiple myeloma (standardised mortality ratios 0.86, 0.85, 0.57, and 0.46); death rates were lower than in controls (relative risks 0.99, 0.96, 0.57, and 0.57; 90% confidence intervals all included 1.00). In the period more than 10 years after the initial participation in tests the relative risk of death in participants compared with controls was near unity for all causes (relative risk 0.99 (0.95 to 1.04) and all neoplasms (0.95 (0.87 to 1.04)); it was raised for bladder cancer (2.69 (1.42 to 5.20)) and reduced for cancers of the mouth, tongue, and pharynx (0.45 (0.22 to 0.93)) and for lung cancer (0.85 (0.73 to 0.99)). For leukaemia mortality was equal to that expected from national rates but greater than in controls for both the whole follow up period (1.75 (1.01 to 3.06)) and the period 2-25 years after the tests (3.38 (1.45 to 8.25)). CONCLUSION--Participation in nuclear weapon tests had no detectable effect on expectation of life or on subsequent risk of developing cancer or other fatal diseases. The excess of leukaemia in participants compared with controls seems to be principally due to a chance deficit in the controls, but the possibility that participation in the tests may have caused a small risk of leukaemia in the early years afterwards cannot be ruled out.
'Common Courtesy' and the Elimination of Passive Smoking
Authors: Ronald M. Davis
Journal: JAMA (1990)

The tobacco industry recommends "common courtesy" as the solution to potential conflicts over smoking in public places and as an alternative to policies that restrict or ban smoking. Specifically, the industry suggests that nonsmokers "mention annoyances in a pleasant and friendly manner" and that smokers ask others, "Do you mind if I smoke?" We analyzed data for 22 000 adults who responded to the 1987 National Health Interview Survey of Cancer Epidemiology and Control to determine if common courtesy is being used in passive-smoking situations. Almost half (47%) of smokers said they light up inside public places without asking if others mind. When someone lights up a cigarette inside a public place, only 4% of nonsmokers ask the person not to smoke despite the fact that most nonsmokers consider secondhand smoke harmful and annoying. We compared these data with similar data collected by the Roper Organization in the 1970s and found that smokers today are less likely to smoke inside public places. However, nonsmokers' actions in response to secondhand smoke have changed very little. These findings show that the common courtesy approach endorsed by the tobacco industry is unlikely, by itself, to eliminate exposure to environmental tobacco smoke. Though no one would oppose the use of common courtesy, we conclude that legislative or administrative mechanisms are the only effective strategies to eliminate passive smoking. (<i>JAMA</i>. 1990;263:2208-2210)